Figure 2.

T cell subsets and ferroptosis sensitivity. Pro-inflammatory CD4 T cells, especially Th1 cells, contain more labile iron than Treg cells, express more transferrin receptor (CD71), and signal more through mTORC1. Iron homeostasis of Treg cells depends on the kinase PDK1 and upregulation of ferritin protein to store cellular iron and thereby lower labile iron. Once these cells enter the TME, the metabolic pressures of the environment can influence their metabolic programs and function. Hypoxia and lipid uptake promotes FOXP3 expression, and non-Treg cells can also express FOXP3, increasing Treg-like cells which have some survival advantages in the TME as they are less dependent on mTORC1 signaling and glycolysis. Tregs rely less on GPX4 than CD8 T cells at baseline but do depend on GPX4 expression for survival in tumors, where GPX4 deficiency rewires them to produce IL-1β and mitochondrial superoxide which then promotes Th17 cells.